Discovery of a Potent, Selective, and Brain-Penetrant Checkpoint Kinase 1 Inhibitor, BEN-28010, for the Treatment of Glioblastoma

Glioblastoma
(GBM) patients face a dire prognosis and
alternative
therapeutic options are desperately needed. Inhibition of checkpoint
kinase 1 (CHK1) represents a potential therapeutic strategy for GBM
through regulation of the DNA damage response (DDR) pathway, but no
suitable brain-penetrant CHK1 inhibitors have been reported to date.
In this study, we disclose the discovery and optimization of clinical
candidate 38 (BEN-28010) as a freely brain-penetrant,
potent, and selective CHK1 inhibitor, derived from virtual screening
hit 1. In vivo pharmacological studies
demonstrated efficacy of orally administered 38 in several
GBM CDX and PDX models as a monotherapy and in combination with ionizing
radiation, including improved overall survival in an intracranially
implanted GBM PDX mouse model. Additionally, 38 utilizes
an underrepresented aminoimidazole kinase hinge-binding motif that
may have broader utility within kinase inhibitor drug discovery.